Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial

Abstract

SummaryBackgroundAdvanced colorectal cancer is treated with a combination of cytotoxic drugs and targeted treatments. However, how best to minimise the time spent taking cytotoxic drugs and whether molecular selection can refine this further is unknown. The primary aim of this study was to establish how cetuximab might be safely and effectively added to intermittent chemotherapy.MethodsCOIN-B was an open-label, multicentre, randomised, exploratory phase 2 trial done at 30 hospitals in the UK and one in Cyprus. We enrolled patients with advanced colorectal cancer who had received no previous chemotherapy for metastases. Randomisation was done centrally (by telephone) by the Medical Research Council Clinical Trials Unit using minimisation with a random element. Treatment allocation was not masked. Patients were assigned (1:1) to intermittent chemotherapy plus intermittent cetuximab or to intermittent chemotherapy plus continuous cetuximab. Chemotherapy was FOLFOX (folinic acid and oxaliplatin followed by bolus and infused fluorouracil). Patients in both groups received FOLFOX and weekly cetuximab for 12 weeks, then either had a planned interruption (those taking intermittent cetuximab) or planned maintenance by continuing on weekly cetuximab (continuous cetuximab). On RECIST progression, FOLFOX plus cetuximab or FOLFOX was recommenced for 12 weeks followed by further interruption or maintenance cetuximab, respectively. The primary outcome was failure-free survival at 10 months. The primary analysis population consisted of patients who completed 12 weeks of treatment without progression, death, or leaving the trial. We tested BRAF and NRAS status retrospectively. The trial was registered, ISRCTN38375681.FindingsWe registered 401 patients, 226 of whom were enrolled. Results for 169 with KRAS wild-type are reported here, 78 (46%) assigned to intermittent cetuximab and 91 (54%) to continuous cetuximab. 64 patients assigned to intermittent cetuximab and 66 of those assigned to continuous cetuximab were included in the primary analysis. 10-month failure-free survival was 50% (lower bound of 95% CI 39) in the intermittent group versus 52% (lower bound of 95% CI 41) in the continuous group; median failure-free survival was 12·2 months (95% CI 8·8–15·6) and 14·3 months (10·7–20·4), respectively. The most common grade 3–4 adverse events were skin rash (21 [27%] of 77 patients vs 20 [22%] of 92 patients), neutropenia (22 [29%] vs 30 [33%]), diarrhoea (14 [18%] vs 23 [25%]), and lethargy (20 [26%] vs 19 [21%]).InterpretationCetuximab was safely incorporated in two first-line intermittent chemotherapy strategies. Maintenance of biological monotherapy, with less cytotoxic chemotherapy within the first 6 months, in molecularly selected patients is promising and should be validated in phase 3 trials.FundingUK Medical Research Council, Merck KGaA.

Effect of Application and Intensity of Bevacizumab-based Maintenance After Induction Chemotherapy With Bevacizumab for Metastatic Colorectal Cancer: A Meta-analysis

“…11,12,17,18 The results from the present analysis do not allow for conclusions regarding the comparative value of bevacizumab versus fluoropyrimidines or the effect of EGFR antibodies in this setting. The discussed maintenance approach has generally been limited to an oxaliplatin-based regimen, although a small number of patients receiving an irinotecan-based induction regimen were included in the SAKK 41/06 (about 30%) and the OPTIMOX 3/DREAM trials.…”

“…[10][11][12]14,15,[17][18][19] Of these, 5 trials were selected for additional analysis, because these trials evaluated a separately defined "maintenance phase," with randomization after the induction phase ( . The selected studies were assessed for potential bias with regard to the randomization approach, timely parallel enrollment, similarity of treatment groups, data-driven reporting, analysis population (intent-to-treat [ITT] vs. other), and other aspects.…”

“…[7][8][9] Recent trials allocated patients after 3 to 6 months of induction treatment to different maintenance strategies and/or observation alone. [10][11][12][13][14][15][16] These trials all showed an effect on progression-free survival (PFS) or the respective alternate endpoints eg, time to failure of strategy or time to second progression; however, the effect on OS has remained unclear. The current meta-analysis was performed to compare observation alone with bevacizumab or bevacizumab and chemotherapy maintenance after induction chemotherapy in terms of PFS and OS.…”

Chemotherapy for previously unresectable colorectal metastases: Multi-line strategies and targeted therapies

“…L'essai randomisé de phase II COIN-B a comparé un traitement d'entretien par cetuximab à une pause thérapeutique complète chez 226 patients (dont 169 avec CRC KRAS sauvage) après une chimiothérapie d'induction de 12 semaines par FOLFOX-cetuximab, en termes de taux d'échec de la stratégie à dix mois [18]. Chez les 130 malades non progressifs à l'issue des trois mois de trithérapie, ce taux était de 52 % dans le bras traité par cetuximab vs 50 % dans le bras sans traitement d'entretien.…”

Maintenance Therapy for Colorectal Cancer: Which Regimen and Which Patients?

“…Additionally, in a study evaluating the long-term effects of oxaliplatin-induced neuropathy, 41 % of patients had persistent grade 2/3 neuropathy during a follow-up period of 25 months even after discontinuation of oxaliplatin [6]. Therefore, several studies have evaluated the role of maintenance therapy with less intensive regimens in patients who experienced stable disease or treatment response following induction therapy as a strategy to reduce toxicity and improve quality of life [7][8][9][10][11][12][13][14][15][16][17][18][19]. The success of such a strategy, however, requires assurance that survival would not be compromised.…”